FOOD-BASED STRATEGIES TO MODULATE THE COMPOSITION OF THE INTESTINAL MICROBIOTAAND THEIR ASSOCIATED HEALTH EFFECTS

8/11/2019 FOOD-BASED STRATEGIES TO MODULATE THE COMPOSITION OF THE INTESTINAL MICROBIOTAAND THEIR ASSOCIAT

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INTRODUCTION

The term 'prebiotic' was first defined in 1995 by Gibson and

Roberfroid as 'a non-digestible food ingredient that selectivelystimulates growth and/or activity of one or a limited number of

bacteria in the colon, thereby improving host health'. As research

progressed, three criteria were accepted which a food ingredientshould fulfil before it can be classified as prebiotic: firstly, it

should be non-digestible and resistant to gastric acidity,hydrolysis by intestinal (brush border/pancreatic) digestive

enzymes, and gastrointestinal absorption; secondly, it should be

fermentable and; thirdly, it should in a selective way stimulategrowth and/or metabolic activity of intestinal bacteria that are

associated with health and wellbeing (1). Well establishedprebiotic compounds nowadays are inulin and oligofructose (or

fructo-oligosaccharides), galacto-oligosacchardies and lactulose,

however extensive research is ongoing to strengthen thescientific basis of promising new candidates.

Inulin-type fructans are naturally occurring oligosaccharidesthat represent the carbohydrate reserve in plants. Plants

containing inulin-type fructans primarily belong to the Liliales,

e.g. leek, onion, garlic and asparagus; or the Compositae, such as

Jerusalem artichoke (Helianthus tuberosus), dahlia and chicory(Cichorium intybus). Inulin is a polydisperse carbohydrate

material consisting of (2 ->1) fructosyl - fructose links (Fig. 1).A starting glucose moiety can be present. Inulin-type fructans can

be represented as both GFn and Fm. In chicory inulin, the number

of fructose units linked to a terminal glucose can vary from 2 to70 units. By means of an endo-inulinase inulin is hydrolysed into

a DP between 2 and 8 (average DP=4) called oligofructose.Other interesting classes of dietary substances that arrive to

a great extent in the colon and are metabolised by the microbiota

in the colon are the polyphenols. Most polyphenols are in theform of esters, glycosides or polymers (proanthocyanidins) and

have to be hydrolysed by intestinal enzymes or by the colonicmicroflora before absorption can occur (2-6). This complex

group of plant derived-polyphenolic compounds has been the

focus of much research given their interesting anti-oxidantproperties which have been related to the protecting effect of

diets rich in fruits and vegetables against several chronicdiseases such as cardiovascular diseases and certain cancers (2,

7). Polyphenols can be classified in different groups including

JOURNAL OF PHYSIOLOGY AND PHARMACOLOGY 2009, 60, Suppl 6, 5-11

www.jpp.krakow.pl

Review article

D. BOSSCHER, A. BREYNAERT, L. PIETERS, N. HERMANS

FOOD-BASED STRATEGIES TO MODULATE THE COMPOSITION OF THE INTESTINALMICROBIOTA AND THEIR ASSOCIATED HEALTH EFFECTS

University of Antwerp, Department of Pharmaceutical Sciences, Laboratory of Functional Food Science and Nutrition, Antwerp, Belgium

The most well known food-based strategies to modulate the composition of the intestinal microbiota are the dietary useof prebiotics, probiotics and their combination, synbiotics. Currently established prebiotic compounds are mainly

targeting the bifidobacteria population of the colon microbiota. A good illustration of the importance of high colonicbifidobacteria levels is the observation that breast milk creates an environment in the colon (because of its high amountin galacto-oligosaccharides with prebiotic activity) favouring the development of a simple flora, dominated by

bifidobacteria to which various health benefits have been ascribed. Currently, high colonic bifidobacteria levels has beenconsidered favourably at all ages and strategies to augment their presence have been demonstrated in placebo-controlled

intervention studies; e.g. in toddlers to reduce sickness events, in adults to reduce the risk for developing gastrointestinal

diseases and in the elderly to re-enhance their declining immune activity. The intestinal microbiota can be considered asa metabolically adaptable and rapidly renewable organ of the body. However, unbalances in its microbial community and

activities are found to be implicated in disease initiation and progression, such as chronic inflammatory bowel diseasesand colonic cancers. Restoration of this balance by increasing bifidobacteria levels has demonstrated to reduce disease

severity of patients and to improve well-being in healtly volunteers. New emerging evidence on the difference in the

composition of the colonic microbiota between obese and lean volunteers has opened new areas for pre-, pro- andsynbiotic research. Additionally, as knowledge will increase about the microbial bio-conversion of polyphenolic

compounds into bioactive metabolites in the colon and whether food-based strategies can augment such bioconversion

into more potent compounds with anti-oxidant and/or anti-inflammatory activity new areas of research will be discovered.This paper provides an up-to-date review of the health benefits associated to the induction of high bifidobacteria levels inthe colon by the use of prebiotics (inulin and oligofructose). New areas of emerging science will be discussed as well.

K e y w o r d s : inulin-type fructans, prebiotics, intestinal microbiota, obesity, phytonutrient metabolisation


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phenolic acids (hydroxybenzoic acids and hydroxycinnamicacids), flavonoids and the less common stilbenes and lignans.

The flavonoids can be further divided in flavones, isoflavones,

anthocyanidins, flavanones, flavanols and their polymers theproanthocyanidins (Fig. 2). The main dietary sources are fruits

(e.g. citrus fruit, apples, grapes and berries), wine, tea, soy andcacao. Polyphenols are also found in vegetables (e.g. onions,

artichokes) but are less abundant. Foods mostly contain complexmixtures of polyphenols (2, 3, 8, 9). To understand their impact

on human health, their nature, origin, amount in the diet,

bioavailability and microbial metabolisation in the colon need tobe investigated. In this respect, gaining understanding of the

metabolisation pathways of polyphenols by the microbiota andthe kind of bioactive metabolites that are formed during this

process is of paramount importance. Also in turn, the effects of

such metabolites on the composition of the microbiota might besubject of investigation. As such, in the future, strategies that

enhance bioactive formation by colonic microbiota manipulation

could be an important tool to enhance anti-oxidant or anti-inflammatory properties of polyphenols.

INTESTINAL FUNCTION, METABOLISM

AND MICROBIOTA

Studies in ileostomised volunteers have demonstrated thatorally ingested inulin enters the colon almost quantitatively

(>90%) where it is subsequently completely metabolized by the

endogenous colonic microbiota (10). In the colon, inulin-typefructans are completely converted by the microbiota into

bacterial biomass, organic acids, like lactic acid and short-chainfatty acids (SCFA: acetic, propionic and butyric acid) and

gasses (CO2, H2, CH4). SCFA and lactate contribute to the host'senergy metabolism.

Inulin-type fructans, through their presence and subsequent

fermentation in the large bowel, influence the colonicmetabolism in its lumen and the integrity and functioning of the

epithelial cell lining. Apart from their stool bulking effect which

has been demonstrated in randomised, double-blind andplacebo-controlled human studies in subjects with low stool

frequency patterns or constipated patients (11-13), more recentlyalso a significant decrease in the intensity of digestive disorders

in patients with minor functional disorders was found in arandomised and double-blind controlled, multicentre study set-

up (14). An increase in stool frequency with the administration

of a synbiotic supplement (Bifidobacterium animalis and anoligofructose-enriched inulin) has been demonstrated in elderly

subjects also to be associated with an improved well-being andthe quality of life (15 - CROWNALIFE project, 'Crown of Life'

Project on Functional Foods, Gut Microflora and healthyAgeing, QLK1-2000-00067).

The intestinal microbiota can be considered as a

metabolically adaptable and rapidly renewable organ of thebody. Administration of oligofructose to post-weaning infants

has been shown to increase the numbers of bifidobacteria (up to9.5 log of colony-forming units per gram of faeces) (16). Also in

adults and elderly subjects, administration of inulin and

oligofructose alone or as synbiotic has been demonstrated toselectively increase numbers of bifidobacteria in the luminal as

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Fig. 1. Chemical structure of inulin compounds.

Fig. 2. Subclasses of flavonoids.


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diarrhea, oligofructose suppressed the presence of pathogens and

increased lactobacilli numbers (33).Clinical studies in humans have also shown that inulin-type

fructans can protect against pathogen colonization and infection.Critically ill patients have a gut microbial ecology that is in

dysbalance and is characterized by high numbers of potential

pathogens. Such patients, at risk for developing sepsis (at

intensive care unit), when receiving oligofructose (as asynbiotic), had lower numbers of pathogens in their nasogastricaspirates. Treatment with antibiotics, on the other hand, also

changes the gut microflora and disrupts normal ecological

balance, which often leads to antibiotic-associated diarrhea. Inthe study of Orrhage et al. antibiotic treatment of patients induced

a marked decrease in the anaerobic microflora, mainly with a lossof bifidobacteria and an overgrowth in enterococci. Oligofructose

administration (as synbiotic) in those patients restored theirnumbers of lactobacilli and bifidobacteria (34). Also, in patients

with Clostridium difficile-associated diarrhea, which frequently

occurs after antibiotic-therapy, oligofructose suppressedcolonization with C. difficile and increased bifidobacteria levels.

These changes were accompanied with a lower relapse of

diarrhea and reduced length of hospital stay (35).Chronic inflammatory bowel diseases such as ulcerative

colitis, Crohn's disease and pouchitis are though to have theiretiology to some extent linked to the composition of the colonic

microbial community and its activities. Although members ofthe gut microbiota normally do not induce disease, in genetically

susceptible hosts, an altered immune response towards normal

commensal organisms is estimated to drive the inflammatoryprocess towards a state of chronic inflammation (36). The effect

of inulin-type fructans in modulating the disease process hasbeen repeatedly demonstrated in experimental models in which

inflammation was induced by chemical agents such as DSS (37)or TNBS (38). In each of these, administration of inulin-type

fructans (alone or as symbiotic) to the diets of animals reduced

the inflammatory process (e.g. MPO, IF-, PGE2), improvedclinical and histological markers with a reduction in

corresponding lesions. The HLA-B27 transgenic (TG) rat is awell-characterised model of chronic intestinal inflammation.

The model spontaneously develops colitis. Oral administration

of oligofructose-enriched inulin to HLA-B27 TG rats decreasedgross cecal and inflammatory histological scores in the caecum

and colon and altered mucosal cytokine profiles (decreased IL-1 and increased TGF- levels). Cytokine responses of

mesenteric lymph node (MLN) cells were also studied in vitro

by their response to cecal bacterial lysates (CBL). Stimulation ofMLN cells by CBL from oligofructose-enriched inulin-treated

TG rats induced a lower interferon- response (39).In humans suffering from ulcerative colitis, it has been

described that bifidobacteria populations are about 30-fold lowercompared to that in healthy individuals. This let to the hypothesis

that restoring bifidobacteria populations in these patients by the use

of pre- or synbiotics may influence the disease process.Supplementation of the diet of patients with ulcerative colitis with

oligofructose-enriched inulin together with a probiotic(Bifidobacterium longum) for 1 month resulted in a 42-fold

increase in bifidobacteria numbers in mucosal biopsies. Clinical

intervention study in ulcerative patients supplemented with thesame synbiotic as indicated above; showed improvement of the

clinical appearance of chronic inflammation, evidenced by areduction in sigmoidoscopy scores, reduction in acute

inflammatory activity (TNF- and IL1-) and regeneration of the

epithelial tissue (40). In another placebo-controlled clinical trial inpatients with ulcerative colitis, oligofructose-enriched inulin

lowered the levels of calprotectin in the faeces thereby improvingthe patients' response to therapy by mitigating intestinal

inflammation (41). Areduction of the inflammation and associated

factors was observed also in patients with an ileal pouch-anal

anastomosis after therapy with inulin-type fructans (42). Moreover,in patients with active ileo-colonic Crohn's disease, dietary

intervention with a combination of inulin and oligofructose hasbeen shown to lead towards an improvement of the disease activity

(reduction in Harvey Bradshaw Index) and enhanced lamina

propria denritic cell IL-10 production and TLR2 and TLR4

expression. Strikingly different changes in mucosa microbiotafollowing inulin supplementation were observed between patientswho entered remission and those that did not. Patients who entered

remission had an increase in mucosal levels of bifidobacteria (43).

MICROBIOTA AND COLONIC CANCER

Diet has a strong influence on the etiology of colorectalcancers and intestinal bacterial metabolism can generate

substances derived from food with genotoxic, carcinogenic, and

tumour-promoting potential. Administration of weanling rats withdifferent types of inulin-type fructans induced a reduction in the

number of aberrant crypt foci (ACF) in the proximal, distal and

total colon. ACF are pre-neoplastic lesions found in the etiologyof most colon cancers. Such reductions in the distal parts of the

colon (and the whole colon) were most pronounced when ratswere fed oligofructose-enriched inulin and resulted in the lowest

numbers of colonic ACF (44). Long-term studies with probiotics,prebiotics and synbiotics in rats with AOM-induced colon cancer

showed a reduction in the number of colon carcinomas when

supplemented with oligofructose-enriched inulin either alone orgiven as a synbiotic (with Lactobacillus rhamnosus GG andbifidobacterium lactis Bb12) (45). Treatment with the carcinogenAOM suppressed the rats' natural killer (NK-) cytotoxicity in the

Peyer's patches (PP). NK cells are involved in both the recognitionand subsequent elimination of tumour cells. Suppression of this

NK-cell activity may subsequently contribute to tumour growth.

Interestingly, the changes in tumour formation upon theintervention coincided with a stimulation of immune functions

within the gut-associated lymphoid tissue (GALT) and PP whichare the primary lymphoid tissues responsive upon oral intake of

prebiotics or synbiotics. The supplementation with oligofructose-

enriched inulin (alone or as a synbiotic) prevented suchcarcinogen-induced NK-cell suppression in PP. After 33 weeks of

treatment, immunological investigation of the rat's PP revealedsignificant higher NK cell-like activity after intake of the pre- or

synbiotic. Other immunological markers in PP cells that differed

upon both interventions were the stimulation in IL-10 production.This increase in IL-10 cytokine production in PP was also found

in a previous study of the same authors after short-term exposureof AOM-rats to prebiotics, probiotics and synbiotics (45).

A phase-II anticancer study, randomised, double-blind andplacebo-controlled in 80 patients with a history of colon cancer orpolyps, and supplemented with a synbiotic (oligofructose-

enriched inulin and Bifidobacterium lactis Bb12 andLactobacillus rhamnosus GG) for 12 weeks, showed increased

levels of bifidobacteria and lactobacilli. This was accompanied bya decrease in the numbers of pathogens (coliforms andClostridium perfringens). The altered composition of the colonic

bacterial ecosystem beneficially affected the metabolic activity inthis organ. This was obvious from the decreased DNA damage in

the colonic mucosa (measured by the comet assay) and thetendency to lower the level of colorectal proliferation (surrogate

biomarker for colon cancer risk) in polyp patients (no measures

were taken in cancer patients). Other effects were the decreasedcytotoxicity of the faecal water. The fecal water of synbiotic-fed

polyp patients also showed a lower level of cell necrosis asdemonstrated by the lower cytotoxic potential in (HCT116 cell

types). This indicates that the synbiotic effectively prevented cell

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death of the colonic epithelium (26 - SYNCAN project,

Synbiotics and Cancer Prevention started, QLK-1999-00346).

INTESTINAL MICROBIOTA, ADIPOSE

TISSUE AND INFLAMMATION

Obesity and metabolic disorders (insulin resistance,hyperlipaemia) are tightly linked to a chronic low-grade state ofinflammation (elevated levels of circulating inflammatory

markers such as IL-6, and C-reactive protein). It is hypothesized

that an altered gut microbiota in the obese state could contributetowards low grade inflammation resulting in the development of

metabolic diseases associated with the condition (e.g. diabetes,cardiovascular disease, etc.) (46). However, the factors

triggering such metabolic alterations remain to be determined.In the obese lower levels of Bacteroidetes and higher levels

of the phylum Firmicutes in the colonic microbiota as compared

to lean counterparts are found (47). These observations have beenassociated with increased gut fermentation and calorific

bioavailability to the host. Moreover, feeding high fat diets have

been demonstrated to alter dramatically the microbiotacomposition in mice with reducing the quantities of dominant

Gram-positive groups, e.g.Bifidobacterium spp. andE. rectale -C. coccoides groups, and the murine Gram-negative group,Bacteroides MB (48). Recent studies in animal models haveshown that such changes within the microbial ecology or

functional activities of the gut microbiota can induce a metabolic

shift towards a pro-inflammatory phenotype, whole-body, liverand adipose tissue weight gain and impaired glucose metabolism.

Factors of microbial origins (e.g. bacterial lipopolysaccharides)are hypothesized to lie at the basis of such effects. In mice, high-

fat feeding let to (low level of) metabolic endotoxemia, lowinflammatory tone, increasing macrophage infiltration in adipose

tissue and dysregulating lipid and glucose metabolism. Multiple

correlation analyses showed that the level of endotoxaemia wasnegatively correlated with Bifidobacterium spp., but no

relationship was seen between any other bacterial groups. On theother hand, restoration of the levels of bifidobacteria in the

intestine of mice upon oligofructose supplementation lowered

endotoxaemia and the level of microbial toxins and improvedmucosal barrier function. Interestingly, the lower body weight

and visceral adipose tissue mass in the oligofructose group(compared with the not supplemented high-fat fed mice) showed

a positive correlation with the endotoxin plasma levels and

negatively with the levels of bifidobacteria. Moreover, levels ofmRNA of IL-1, TNF-, and plasminogen activator inhibitor type-

1 (Pai-1, or Serpine-1) in adipose tissue were increased in high-fat fed mice, whereas the levels were blunted with oligofructose

feeding. In addition, a normalisation of IL-1 and IL-6 cytokineswas observed upon oligofructose feeding. These data indicate

that a lower fat mass and body weight 'only' are not a prerequisite

for a lower inflammatory tone and that this effect is accompaniedby prebiotic changes in the microbiota. Plasma cytokines were

positively correlated with plasma endotoxin levels and negativelywith bifidobacteria levels (48). In diabetic mice, feeding

oligofructose reduced hepatic levels of phosphorylate IKK- and

NFB, suggestive of a reduction in the hepatic inflammatorystatus which might relate to an improvement of the insulin

sensitivity (49).

MICROBIOTA AND INTESTINAL METABOLISATIONOF PHYTONUTRIENTS

Polyphenol aglycones and a few glucosides (e.g. quercetin 3-

glucoside) can be absorbed in the intestine, but the efficiency of

polyphenol absorption is generally low and differs widely

depending on the type and structure of the polyphenol. Anextensive review comparing bioavailability and bioefficacy of

polyphenolic compounds showed that polyphenols which havehigh absorption (after intake of 50 mg dose) are gallic acid (Cmax=

4 M), followed by isoflavones glycosides (daidzin, genistin)

(Cmax= 2 M), flavanones and quercetin glucosides.

Proanthocyanidins and anthocyanidins are poorly absorbed(Cmax= 0.02 M) (8). Oral administrations of chlorogenic andcaffeic acid supplements, found that these phenolic acids are

absorbed for about 33 and 95 %, respectively. However,

cholorogenic acid accounts for 0.3% in urine and caffeic acid wasfound for 11% in urine. Thus after absorption chlororgenic and

caffeic acid are metabolised extensively in other compounds (50).Non absorbed polyphenols reach the colon. In the colon, the

microbiota (e.g. Escherichia coli, Bifidobacterium sp.,Lactobacillus sp., Bacteroides sp., Eubacterium sp.) hydrolyses

the glycosides to aglycones, which can further be metabolised to

aromatic acids like phenylacetic, phenylpropionic, phenylvalericand benzoic acid. Those phenolic acids are well absorbed through

the colonic epithelium (2-6). With respect to the bioavailability of

dietary polyphenols and their colonic metabolites, more researchis currently needed in order to clarify the contribution of these

different metabolites to in vivo anti-oxidant efficacy.The importance of the colonic metabolisation has already

been demonstrated for some polyphenolic compounds in differentstudies. First, for the hydroxycinnamic acids, which are naturally

esterified in plant products, metabolisation is carried out by the gut

microflora (2, 3, 51). Bacterial species like Escherichia coli,Bifidobacterium lactis and Lactobacillus gasseri express

cinnamoyl esterase activity and are responsible for the cleavage ofthe ester bond between caffeic and quinic acid in chlorogenic acid

(51). Secondly, regarding the flavonoid group, the microbiotaenzymes fromBacteroides distasonis,B. uniformis andB. ovatus

are important (e.g. -rhamnosidases hydrolyse rutinoside to

quercetin).Enterococcus casseliflavus andEubacterium ramulusmetabolise quercetin-3-O-glucoside to form formate, acetate,

lactate, the aglycone quercetin, butyrate, ethanol and 3,4-dihydroxyphenylacetic acid. Strains belonging to the Clostridium,Bacteroides andEubacteria genera are also mentioned to cleave

the C-ring of quercetin resulting in 3,4-dihydroxyphenylaceticacid and protocatechuic acid (2).Eubacterium ramulus has also an

impact on naringenin, apigenin and the isoflavone genistin (7, 9).In another study, the role of gut microflora in the absorption and

metabolism of isoflavones and lignans was investigated using

germ-free rats and rats associated with human faecal bacteria. Soyand soy products contain the isoflavones genistein and daidzein

usually in the form of glycosides (genistin and daidzin). Germ-free rats fed soy-isoflavone only excrete the aglycones daidzein

and genistein. Hydrolysation of the isoflavone glycosides occursin the proximal intestinal tract. In contrast, the metabolites equol,

O-desmethylangolensin and the lignan enterolactone were only

detectable in the urine of human flora associated (HFA) rats. Thisdemonstrates the importance of the gut microbiota in the

metabolisation of isoflavones and lignans. The colonization ofgerm-free rats with faecal flora from human subjects, capable to

convert daidzein to equol, results in the excretion of the

metabolites. In the urine of HFArats associated with a faecal florafrom a low-equol producing subject no detectable equol quantities

were found. This indicates that some subjects are unable toproduce equol due to the lack of specific components of gut

microbiota (52).

Apart from inter-individual variation in daily intake ofpolyphenols, inter-individual differences in the composition of

the human microbiota may lead to differences in bioavailabilityand bioefficacy of polyphenols and their metabolites. Research

is needed to understand the role of the colonic microflora in the

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metabolisation of polyphenols and to evaluate the biological

effects, including the anti-oxidative effects of these microbialmetabolites.

In this respect, dietary strategies that modulate thecomposition of the microbiota enhancing metabolisation of

polyphenols are hypothesized to improve bioavailability of

polyphenols and could potentate their activity. In ovariectomized

rats, feeding simultaneously soy isoflavones and fructo-oligosaccharides increased plasma levels of genistein, daidzein,and equol compared to isoflavone feeding alone. This effect also

maximised the protective effects of isoflavones agains gonadal

induced osteopenia (53). Inulin-type fructans have also beenshown to increase plasma and urinary concentrations of soy-

derived genistein and daidzein and their aglycone forms inhumans. In post-menopausal women who were asked to consume

a conjugated form of soybean isoflavones together with inulin itwas found that 24 hr plasma levels (measured as the area under

the curve) were resp. 38% for daidzein and 91% for genistein

higher when compared to the isoflavone intake alone (54).

OUTLOOK AND PERSPECTIVES

The number of publications about food-based strategies tomodulate the composition of the microbiota and their associated

health effects has increased steadily over the last decade. This isexpecting to continue since the importance of a well balanced

colonic microbiota and its activities, as being a key factor in the

modulation of human immunity, anti-oxidant defence,metabolism and endocrine activities, is more and more

recognized. As new insights are being elucidated about thecomposition of the microbiota and its species diversity, the

metabolic pathways of substrate degradation and the role inhealth and disease, interest will continue to rise. Together with

this, it is of paramount importance to develop strategies to

modulate this microbiota in a way to reduce the risk ofdeveloping disease through dietary means and the use of

functional foods offers great value in this regard.

Conflict of interests: None declared.

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Re c ei v ed : September 9, 2009A c ce p t e d : November 30, 2009

Authors address: Dr. Douwina Bosscher, University of

Antwerp, Department of Pharmaceutical Sciences, Laboratory

of Functional Food Science and Nutrition, Wilrijk, Belgium;E-mail: [email protected]

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FOOD-BASED STRATEGIES TO MODULATE THE COMPOSITION OF THE INTESTINAL MICROBIOTAAND THEIR ASSOCIATED HEALTH EFFECTS